Robbins Chapter on Neoplasia Flashcards
What are the two most common general epigenetic changes we see in cancer and what do they do to genes?
DNA Methylation: Silence gene expression
Histone modification: Can enhance or dampen gene response
Discuss what oncogenes and oncoproteins are and what they do
Oncogenes are created by mutations in proto-oncogenes and encode proteins called oncoproteins that have the ability to promote cell growth in the absence of normal growth-promoting signals
These oncoproteins are usually close to identical to the normal protein products but tend to have internal regulators shut off so that the external environment doesn’t shut them off
Discuss the pathway of growth factor receptors that is absolutely key to understanding the biochemistry of cancer (just about 100% of cancers are due to effects in this pathway)
Basically, growth factor receptors get a signal from a growth factor that causes Inactive RAS to activate. Active RAS activates RAF, which activates MAPK leading to activation of transcription, causing upregulation of MYC (Progrowth metabolism and increased protein synthesis) and D cyclins (cell cycle progression).
Active RAS also activates PI3K which turns on AKT (helps progrowth metabolism) which turns on mTOR (helps protein synthesis).
These changes cause cell growth
GAP turns the Active RAS to Inactive and PTEN stops PI3K progression
In regards to any cancer involving the epithelium, there is a stepwise mechanism involved in turning that epithelium unto a metastasis. Each of these events is associated with a genetic alteration. Discuss this stepwise progression.
So we have normal epithelium. With activation of the Wnt pathway due to APC, we turn this normal epithelium to an early adenoma or dysplastic crypt.
EGFR signaling via a KRAS mutation then occurs, turning this early change into an intermediate adenoma.
Intermediate gets turned to late adenoma via inactivation of TGF-B due to a Smad 2/4 mutation (this is not terribly high yield)
We get carcinoma finally because of a loss in p53, and eventually, due to other genetic alterations, this carcinoma metastasizes.
What is BRAF and what is it linked to
BRAF: Hairy Cell Leukemia, melanoma, benign nevi
Serine/threonine protein kinase of the MAPK family. Activating mutation for pro-growth
Discuss the common mutation we see with the ABL Tyrosine kinase and what it leads to
In CML, ABL tyrosine kinase from Chromosome 9 translocates to Chromosome 22 and fuses with BCR, getting constitutively activated. Interestingly, even though CML is associated with a ton of other gene issues and receptor issues, blocking this BCR-ABL kinase with designer drugs can be extremely effective in stopping replication of CML. We call a weakness like this an “oncogene addiction”
Discuss what MYC is and what it is linked to
MYC: A transcription factor: Increased expression of this causes disregulatino of cell growth (Burkitt Lymphoma and other hematologic malingnancies), gene amplification (neuroblastoma) and increased activity of upstream signaling pathways (a bunch of cancers)
What is CDK4?
CDK4: Cyclin dependent kinase. Mutation promotes cell cycle progression
What does RB do and how is it linked to cancer?
RB: When hypophosphorylated, RB exerts antiproliferative effects by binding to and inhibiting E2F transcription factors that regulate genes required for cells to pass through the G1-S phase checkpoint.
We normally hyperphosphorylate (inactivate) this to progress cell cycle when needed. Cancers cause loss of function in the RB allele to stop its antiproliferative effects.
What four issues can occur with the RB pathway to cause cancer
Loss of function mutations of RB
Gene amplification of CDK4 and Cyclin D genes
Loss of cyclin-dependent kinase inhibitors (p16 and INK4A)
Viral oncoproteins that bind and inhibit RB (E7 protein of HPV)
Discuss the importance of p53 and its link to cancer (the specific pathway)
p53 protein - Central monitor of stress in the cell and is activated by anoxia, mutated oncoproteins or damaged DNA. DNA damage is sensed by complexes containing kinases of the ATM/ATR family, and they phosphorylate p53, liberating it from inhibitors like MDM2. Active p53 then upregulates the expression of proteins like CDK inhibitor p21, thereby causing the arrest of the cell cycle at G1-S checkpoint, allowing for repair of the damaged DNA. No repair capable = p53 induced apoptosis
What do we see with APC issues?
APC - Encodes a factor that negatively regulates the WNT pathway in colonic epithelium by promoting the formation of a complex that degrades B-catenin. FAP with loss of a single allele and colon carcinoma with both alleles.
Importance of E-cadherin?
E-cadherin - Loss of function = gastric carcinoma due to loss of contact inhibition (cells touching each other need to stop replicating)
Importance of CDKN2A
CDKN2A - Encodes two tumor suppressor proteins: p16/INK4A that augments RB function and ARF which stabilizes p53. Germline loss of function = familial melanoma. Both leads to leukemias, melanomas, etc.
How is TGF-B linked to cancer?
TGF-B: Potent inhibitor of cellular proliferation. Mutations lead to immune evasiveness in cancer and proliferation of various cancers
